Transdermal therapeutic system (TTS) containing vitamin E for the treatment of drug dependency

ABSTRACT

The invention relates to a transdermal therapeutic system (TTS) for the administration of active agents for substitution treatment of drug dependency or drug addiction.

FIELD OF INVENTION

The present invention relates to the transdermal administration ofsubstances which are suited for substitution treatment of drugdependents and drug addicts, in particular to the structure of atransdermal therapeutic system (TTS) and a method for administration ofsuch substances through intact skin. Concerning the suited substances,one could contemplate for example methadone, acetylmethadol, naltrexon,codeine or dihydrocodeine. In principle, the application of otherstrongly effective pain relievers is possible, for example morphine orbuprenorphine. Methadone, mentioned as an example, is used insubstitution therapy for opiate addicts, for example heroin addicts. Oneuses the L-enantiomorph as hydrochloride in the form of an aqueoussolution, which is applied orally. The strongly analgesic effect ofmethadone is also used for drug dependent AIDS patients.

BACKGROUND OF INVENTION

Transdermal therapeutic systems for combating drug dependency and drugaddiction are known, for example WO-A-9 219 226, WO-A-9 410 987, EP-B-0113 562, EP-B-0 117 027 and EP-B-0 280 413.

The document WO-A-9 219 226 describes an application system containinglobeline for combating drug dependency. WO-A-9 410 987 relates to acombination of two application systems containing methadone. In EP-B-0113 562, a container is suggested with which methadone can be appliedthrough the skin. EP-B-0 117 027 describes a salve, a cream or a gelwith an amount of methadone. Finally, a pharmaceutical composition issuggested in EP-B-0 280 413 for transdermal application of methadonewith the aid of a permeation accelerator.

In principle, a transdermal administration of methadone andcorresponding substances is preferable over an oral or parenteralapplication. It is apparent that a transdermal therapeutic system. (TTS)offers much greater security with respect to abusive use. For example,extraction of the drug from the TTS matrix without skilled knowledge isnot possible. An abusive parenteral application by an addict to obtainsatisfaction is much less of a danger than for example a solutionadministered orally.

A therapy using transdermal therapeutic systems can be carried outwithout direct supervision or without a doctor. A further advantage isthe direct control of the dosage by means of the permeation surface. Inwithdrawal therapy, the necessary dosages can be adapted to theindividual needs of the addict in simple manner. The known advantages ofa transdermal application are also present, namely

avoidance of the high dosage necessary for oral application, whichaccommodates the first-pass effect, and better control of the bloodvalues.

The document DE-A4 339 400 describes a drug plaster in the form of alaminate, which includes a carrier and a matrix of a single polymer andan amount of vitamin E or a vitamin E derivative as well as at least oneactive agent, which can be an analgesic agent. The flux J of the activeagent through a membrane of defined thickness, for example through theskin, should follow the equation:

    J=diffusion coefficient D×diffusion surface A×distribution coefficient K×agent concentration on the donor side of the membrane C.sub.o /membrane thickness h.

SUMMARY OF INVENTION

The agent flux J is thus proportional to the agent concentration C_(o).However, if one would replace an oral application, for example ofmethadone, by a transdermal application and if one will avoid lowmolecular alcohols as permeation promoters, then (even apart from thefirst-pass effect) such a high agent concentration would be necessarythat DE5-A4 339 400 could not offer a solution.

The object of the present invention is solved with a transdermaltherapeutic system (TTS) for the administration of methadone in the formof a racemate (D,L-methadone) or one of its enantiomers, acetylmethadolin the form of its racemate (D,L-Acetylmethadol) or one of itsenantiomers, naltrexon, codeine, dihydrocodeine, morphine, buprenorphineand/or one of their pharmaceutically acceptable salts as the activeagent. The system for the treatment of drug dependency or drug addictionis provided with

a self-adhesive layer-like matrix containing an amount of active agentor agents, where on or over one side of the matrix is provided

a cover foil (backing liner) and on or over the other side of the matrix

a release foil (release liner) is provided.

Further, the object of the present invention is solved by a transdermaltherapeutic system (TTS) for the administration of methadone in the formof a racemate (D,L-methadone) or one of its enantiomers, acetylmethadolin the form of its racemate (D,L-acetylmethadol) or one of itsenantiomers, naltrexon, codeine, dihydrocodeine, morphine, buprenorphineand/or one of their pharmaceutically acceptable salts as the activeagent for the treatment of drug dependency or drug addiction. The systemcomprises an outer backing liner, a reservoir for the active agent, anadhesive element for skin contact of the plaster and a removableprotection layer, where the reservoir, apart from the active agent,optionally includes permeation promoters, emulsifiers, thickening agentsand/or common additives. According to Hadgraft & Wolff, Physicochemicaland pharmacokinetic parameters affecting percutaneous absorption inDermal and Transdermal-Drug Delivery, volume 31 (1993), pages 161, APVpaperback, the diffusion law of Fick would be applicable for masstransport through homogeneous membranes such as the skin. The equationdescribes a linear relationship between the flux J and the concentrationin the vehicle C_(o) under steady state conditions.

    J=KDA(C.sub.o -C.sub.s)/h=kp delta C

    ______________________________________                                        J    flux, for example in μg/cm.sup.2 /h                                   K    distribution coefficient of the membrane (skin)/vehicle                       (dimensionless)                                                          kp   permeability coefficient (cm/h)                                          D    diffusion coefficient in the membrane (cm.sup.2 /s)                      A    permeation surface area(cm.sup.2)                                        h    membrane thickness (cm)                                                  C.sub.v                                                                            concentration in the vehicle                                             C.sub.s                                                                            concentration in the membrane under sink conditions (i.e. continual           transport of the agent from the membrane).                               ______________________________________                                    

In the experiments underlying the present invention, it was surprisinglyfound that for example with L-methadone as the agent, the amount ofagent which permeates in an in vitro test with mouse skin did notincrease linearly with the increase in agent concentration in thematrix, but was overproportional or greater than linear. This issurprising, because it could not be expected from the prior art that atransdermal therapeutic system, for example with L-methadone as theactive agent, would deliver a permeation rate as high as that requiredfor a rational transdermal therapy with amounts of 10 to 15 mg/day.

The active agents contemplated include for example methadone in the formof a racemate (D,L-methadone) or one of its enantiomers, acetylmethadolin the form of its racemate (D,L-acetylmethadol) or one of itsenantiomers, naltrexon, codeine, dihydrocodeine, morphine, buprenorphineand/or one of their pharmaceutically acceptable salts. L-methadone ispreferred.

The transdermal therapeutic system according to the present inventioncan be characterized by an amount of at least about 5, preferably about10 and more preferably about 15 weight-% methadone based on the matrixor the reservoir of the plaster ready for application.

Particularly preferred is an amount of 15 to 20 weight-% methadone.

The transdermal therapeutic system according to the present inventioncan also be characterized by a matrix with an additional amount ofvitamin E or a vitamin E derivative, optionally in the form of anoil-base solution, such as D-α-tocopherol.

The amount of oil-based solution can be 5 to 15 weight-% based on thematrix or the reservoir of the plaster ready for application.

The backing liner of the transdermal therapeutic system according to thepresent invention can be made of polyester, polypropylene, polyethyleneor polyurethane, in each case optionally metallized, and the releaselining can be made of polyester, polypropylene or coated paper.

For the matrix of the transdermal therapeutic system according to thepresent invention is contemplated a pressure adhesive or melt adhesiveon the basis of polyacrylate, polyisobutylene, silicone,styrene-butadiene copolymer or styrene-isoprene copolymer, where forsilicone Durotak(?) is particularly preferred.

The transdermal therapeutic system according to the present inventioncan be characterized by a semi-permeable membrane, in particular amembrane which controls the agent permeation.

The reservoir in the present transdermal therapeutic system can beformed by the backing liner or cover layer and the membrane or by amatrix. The membrane can be provided on the basis of silicone,polypropylene or polyvinyl acetate. The adhesive element according tothe present transdermal therapeutic system can be provided in the formof a reservoir (when no membrane is provided) or in the form of a layercompletely covering the membrane or only on its periphery. A pressuresensitive adhesive based on silicone can be used for the adhesiveelement.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a preferred embodiment of the present invention.

FIG. 2 shows a graphical representation of the relationship between fluxand agent concentration in the matrix.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The invention will be described in more detail in the following inconjunction with the figures and examples.

A matrix system is provided for example as shown in FIG. 1, where theactive agent is dissolved in a self-adhesive matrix 2, whichsimultaneously accomplishes intensive contact with the skin and adhesionto the skin. The plaster comprises a backing liner 1 which is coatedwith the agent matrix 2. The backing liner 1 can be made of polyester(PETP), where alternative materials can be used including polypropylene,polyethylene or polyurethane of arbitrary thickness (for example 10 to100 μm) and optionally metallized (for example with aluminum) andoptionally printed. Furthermore, the plaster according to the inventionis provided with a release liner 3, which is removed before use to thenadhere the plaster onto the skin. The release liner 3 can be made ofpolyester (for example PETP) and can be transparent, opaque or printed.The release liner 3 can also be made of polypropylene or of coatedpaper, where any suitable thickness can be provided, for example 40 to100 μm.

EXAMPLES 1 to 5

Five different plasters according to the invention were produced withthe following characteristics.

Matrix: Durotak which is a PSA pressure adhesive for medical use basedon polyacrylate.

Matrix surface weight: about 80 g/m²

Matrix thickness: 30 to 60 μm

Backing liner: polyester (PETP), namely Hostaphan RN 19

Release liner: polyester (PETP), namely Geiroflex PET 75 μl-s

D-α-tocopherol: free vitamin E concentrate from plant oils with thedesignation Copherol F-1300 (Henkel)

To produce the plaster, L-methadone base material was dissolved in about160 mg acetone to produce a clear solution. In a closed mixing vessel,an amount of Durotak was prepared as can be taken from the followingtable. Thereafter, the tocopherol was added as well as the active agentsolution and mixed for at least one hour.

The obtained solution was applied, for example with a doctor withautomatic guidance, on the release liner at a thickness of 400 to 500 μmand dried for about one hour at about 50° C. Alternatively, the linerwith applied agent matrix could be passed through three drying ovenswith increasing temperature in the range of about 40 to 80° C.

After drying, the backing liner was laminated to the coated releaseliner. The obtained laminate was then cut into strips of 50 to 100 mmwidth. Individual plasters with a surface of 10 to 15 cm² were thenstamped out of these strips. Each stamped-out plaster was then packagedin a four-sided closed envelope of aluminum/polyethylene laminate foil.

    ______________________________________                                        Agent Concentration                                                                          Matrix Composition                                             ______________________________________                                        3% L-methadone L-methadone (base)                                                                          2.4 mg                                                          D-α-tocopherol                                                                        8.0 mg                                                          Durotak 326-1753                                                                            69.6 mg*                                                                     80.0 mg                                           5% L-methadone L-methadone (base)                                                                          4.0 mg                                                          D-α-tocopherol                                                                        8.0 mg                                                          Durotak 326-1753                                                                            68.0 mg*                                                                     80.0 mg                                           10% L-methadone                                                                              L-methadone (base)                                                                          8.0 mg                                                          D-α-tocopherol                                                                        8.0 mg                                                          Durotak 326-1753                                                                            64.0 mg*                                                                     80.0 mg                                           15% L-methadone                                                                              L-methadone (base)                                                                         12.0 mg                                                          D-α-tocopherol                                                                        8.0 mg                                                          Durotak 326-1753                                                                            60.0 mg*                                                                     80.0 mg                                           20% L-methadone                                                                              L-methadone (base)                                                                         16.0 mg                                                          D-α-tocopherol                                                                        8.0 mg                                                          Durotak 326-1753                                                                            56.0 mg*                                                                     80.0 mg                                           ______________________________________                                    

Dry mass, the adhesive was employed in the corresponding amount as asuspension in ethyl acetate with a solids content of about 40%.

The obtained plasters, each with a permeation surface area of 2.5 cm²were then subjected two permeation tests in vitro. The respectiveplasters were applied to the isolated skin of female naked mice, fromwhich the fat tissue under the skin had been removed. In a modifiedFranz diffusion cell, the time dependent permeation of the active agentinto an acceptor medium was measured, namely a 0.9% sodium chloridesolution. As one can derive from FIG. 2, it was surprisingly found thatthe amount of agent permeated through the mouse skin did not increaselinearly with the increase in agent concentration but proportionallygreater than linear.

I claim:
 1. Transdermal therapeutic system (TTS) for the administrationof methadone in the form of its racemate (D,L-methadone) or one of itsenantiomers and/or of their pharmaceutically acceptable salts as theactive agent for treating drug dependency or drug addiction comprisingaself-adhesive layered matrix with an amount of an active agent oragents, and an additional amount of about 10% vitamin E or vitamin Ederivative; a backing liner provided on or over one side of the matrix;and a release liner provided on or over the other side of the matrix. 2.Transdermal therapeutic system according to claim 1, wherein themethadone is L-methadone.
 3. Transdermal therapeutic system according toclaim 1 wherein the amount of methadone comprises 5 weight-% to 20weight-% based on the matrix.
 4. Transdermal therapeutic systemaccording to claim 1 wherein the methadone comprises 15 to 20 weight %.5. Transdermal therapeutic system according to claim 1, wherein thematrix comprises an additional amount of vitamin E or vitamin Ederivative, optionally in the form of an oil-base solution, such asD-α-tocopherol.
 6. Transdermal therapeutic system according to claim 5wherein the oil base solution is 5 to 10 weight % based on the matrix.7. Transdermal therapeutic system according to claim 1, wherein saidmade of polyester, polypropylene, polyethylene or polyurethane,optionally metallized.
 8. Transdermal therapeutic system according toclaim 1, wherein said release liner made of polyester, polypropylene orcoated paper.
 9. Transdermal-therapeutic system according to claim 1wherein the adhesive is selected from the consisting of polyacrylate,polyisobutylene, silicone, styrene-butadiene copolymer orstyrene-isoprene copolymer.
 10. Transdermal therapeutic system accordingto claim 9, wherein the matrix is a polyacrylate adhesive. 11.Transdermal therapeutic system according to clam 1, further comprising asemi-permeable membrane for controlling the active agent permeation. 12.Transdermal therapeutic system according to claim 11, wherein themembrane comprises of silicone, polypropylene or polyvinyl acetate.